..The objective of this study was to determine the relationship between kon, koff and the affinity (Ki) of antipsychotic agents for the D2 receptors, with particular reference to typical and atypical antipsychotic agents...

Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy

..The study provides a rationale as well as clinically comparable dosing regimens for animal studies and raises questions about the inferences drawn from previous studies that have used doses unrepresentative of the clinical situation...

The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats

..1 = 6), olanzapine (0.30/0.43 = 0.7). These results indicate that dissociation between central and peripheral D2 receptor occupancy is a major determinant of the degree of prolactin elevation observed at therapeutic doses...

Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis

S KapurSchizophrenia Program and the PET Centre of the Centre for Addiction and Mental Health, University of Toronto, CanadaAm J Psychiatry 158:360-9. 2001

..Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic "atypical" is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics...

Half a century of antipsychotics and still a central role for dopamine D2 receptors

..Combined serotonin-2/dopamine-2 (5-HT2/D2) antagonism represents one such model, and we now have PET evidence available that can be extrapolated to our understanding and clinical use of both conventional and novel antipsychotics...

A simple method to measure baseline occupancy of neostriatal dopamine D2 receptors by dopamine in vivo in healthy subjects

..Our results question the current reliance on plasma kinetics as the main basis for dosing regimens of antipsychotics. Studies of brain kinetics may provide a sounder basis for determining dosing schedules of psychotropic medications...

Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET

..We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench--using D2 occupancy as a mediating variable--will lead to more valid animal models...

Antipsychoticlike effects of amoxapine, without catalepsy, using the prepulse inhibition of the acoustic startle reflex test in rats

..A review of pharmacologic and behavioral data suggested that amoxapine should also conform to this profile; therefore, we undertook a positron-emission tomography (PET) study of its 5-HT2 and D2 occupancy...

In vivo evidence for dopamine-mediated internalization of D2-receptors after amphetamine: differential findings with [3H]raclopride versus [3H]spiperone

..17 post AMPT). Thus, while DA depletion "uncovers" D(2)receptors, it does not do so for D(1) receptors. The implications of this finding for measuring endogenous DA and its effects on in vivo receptor binding in humans are discussed...

..It is concluded that amphetamine sensitization likely impacts behaviour by altering the functioning of mesolimbic dopamine systems and prefrontal cortical function and can serve as a model of certain domains of schizophrenia...

Neuromodulation of frontal and temporal cortex by intravenous d-fenfluramine: an [15O]H2O PET study in humans

..This seems to be particularly important in individuals experiencing a first episode of schizophrenia, as they appear to be especially responsive to pharmacotherapy and quite sensitive to adverse effects...

Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects

..These results substantiate the use of [11C]-(+)-PHNO as an agonist radiotracer for D2-imaging. The sensitivity of its binding to competition with endogenous DA suggests an association with the subset of high affinity state D2-receptors...

Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models

..The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects, with low motor side effect liability, in a dose range that corresponds to high D2 in vivo occupancy...

Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography

..2-3.5-fold increase of DA D2(High) receptors may explain why amphetamine-sensitized animals are much more sensitive to DA agonists, even though the total density of D2 receptors may apparently be unchanged or even decreased...

..An extended-release (XR) formulation of quetiapine is currently being developed to achieve similar efficacy using a once-daily dosing regimen. We compared the central D(2) receptor binding between the IR and XR formulations...

Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery

..Based on prior data, we predicted that variations in the within-day kinetics of antipsychotic drug delivery would produce different outcomes, even if we held achieved dose, route, and total duration of treatment constant...

'Jumping to conclusions' and delusions in psychosis: relationship and response to treatment

Mahesh MenonSchizophrenia Program and PET Centre, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, CanadaSchizophr Res 98:225-31. 2008

..The findings suggest that JTC might moderate the effects of treatment on symptomatology, but it does not mediate the treatment induced reduction in delusional intensity...

Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study

David MamoDepartment of Psychiatry, University of Toronto, Toronto, CanadaAm J Psychiatry 164:1411-7. 2007

..The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder...

Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans

..This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease...

..We treated patients experiencing their first episode of schizophrenia with a single daily dose of quetiapine to achieve a transient daily peak of D(2) receptor blockade, to determine if this would lead to an antipsychotic response...

Amphetamine-sensitized animals show a sensorimotor gating and neurochemical abnormality similar to that of schizophrenia

..A dose-response relationship between dopamine D(2) occupancy and acute extrapyramidal symptoms (EPS) has been well established. However, the link with the induction of tardive dyskinesia (TD) is less clear...

Effect of acute antipsychotic administration on dopamine synthesis in rodents and human subjects using 6-[18F]-L-m-tyrosine

David MamoDepartment of Psychiatry, University of Toronto, CanadaSynapse 52:153-62. 2004

..Our results suggest that 6-[18F]-L-m-tyrosine PET may not be a useful tool in the study of the effect of antipsychotics on dopamine synthesis in human subjects...

Amphetamine-sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges

..The objective of this study was to determine whether continuous, versus intermittent, olanzapine (OLZ) infusion differently affects the development of VCMs...

Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography

Alan A WilsonPET Centre, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Ontario, CanadaJ Med Chem 48:4153-60. 2005

..Atypical antipsychotics are thought not to elevate prolactin levels. The authors examined data suggesting that atypical antipsychotics do elevate prolactin levels but more transiently than typical antipsychotics...

..The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis...

..The present findings suggest that clozapine may have an important role in the early treatment of first-episode patients whose psychosis does not remit with other second-generation antipsychotics during the first months of treatment...

..To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia...

..Since amoxapine is off-patent, it may be a valuable low-cost alternative to new atypical antipsychotics, particularly in low-income countries where the majority of the patients are still treated with typical antipsychotics...

..The reversal of these deficits by a D1 receptor agonist provides further evidence that prefrontal D1 dopamine receptors are involved in cognition, and may be a potential target for treatment of impaired cognition in schizophrenia...

The effect of antipsychotic treatment on Theory of Mind

Romina MizrahiCentre for Addiction and Mental Health, and Department of Psychiatry, Faculty of Medicine, University of Toronto, Ontario, CanadaPsychol Med 37:595-601. 2007

..However, it remains unclear whether TOM deficits constitute a trait- or a state-related deficit and whether they respond to antipsychotic treatment, and also whether the change in TOM and change in psychosis are associated...

A model of antipsychotic action in conditioned avoidance: a computational approach

..The APD action in this model is most consistent with an effect on 'expected future reward'--an idea closely linked to motivational drives and consistent with several leading theories of dopamine action...